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Clinical Trial Results:
A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Patients Without Inhibitors

Summary
EudraCT number	2016-000072-17
Trial protocol	GB IE ES DE PL FR IT
Global end of trial date

Results information
Results version number	v1
This version publication date	30 Sep 2018
First version publication date	30 Sep 2018
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BH30071

ISRCTN number

US NCT number

NCT02847637

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

15 Sep 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Sep 2017

Global end of trial reached?

Main objective of the trial

The main objective of this study was to evaluate the efficacy of prophylactic emicizumab (1.5 mg/kg/week or 3 mg/kg/2weeks) compared with no prophylaxis in patients with haemophilia A without Factor VIII (FVIII) inhibitors on the basis of the number of bleeds over time.

Protection of trial subjects

This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Sep 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 12

Country: Number of subjects enrolled

Costa Rica: 9

Country: Number of subjects enrolled

France: 9

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Ireland: 4

Country: Number of subjects enrolled

Italy: 12

Country: Number of subjects enrolled

Japan: 19

Country: Number of subjects enrolled

Poland: 13

Country: Number of subjects enrolled

South Africa: 10

Country: Number of subjects enrolled

Korea, Republic of: 4

Country: Number of subjects enrolled

Spain: 14

Country: Number of subjects enrolled

Taiwan: 5

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

United States: 26

Worldwide total number of subjects

152

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

139

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 161 participants were screened, of which 9 failed screening and 152 who previously received either episodic or prophylactic treatment with FVIII agents were enrolled in this study. Participants in Arms A, B, and C were randomized in a 2:2:1 ratio; participants in Arm D were enrolled without randomization.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

C: No Prophylaxis

Arm description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial; they were given the opportunity to switch to emicizumab prophylaxis after completing 24 weeks no prophylaxis.

Arm type

Active comparator

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra, ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

After having completed 24 weeks of episodic factor VIII (FVIII) treatment (no prophylaxis), participants were given the opportunity to switch to emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks followed by a maintenance dose of 3 mg/kg/2 weeks up to the end of study.

A: Emicizumab 1.5 mg/kg/week

Arm description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for 4 weeks, followed by 1.5 mg/kg/week emicizumab SC until the end of study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra, ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week up to the end of study.

B: Emicizumab 3 mg/kg/2 weeks

Arm description

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 mg/kg/week SC for 4 weeks, followed by 3 mg/kg/2 weeks emicizumab SC until the end of study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra, ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks followed by a maintenance dose of 3 mg/kg/2 weeks up to the end of study.

D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)

Arm description

Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg/week SC for 4 weeks, followed by 1.5 mg/kg/week emicizumab SC until the end of study.

Arm type

Experimental

Investigational medicinal product name

Emicizumab

Investigational medicinal product code

RO5534262

Other name

Hemlibra, ACE910

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Emicizumab was administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week up to the end of study.

Number of subjects in period 1	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)
Started	18	36	35	63
Completed 24 weeks on No Prophylaxis	16	0 ^[1]	0	0
Switched to emicizumab 3 mg/kg/2 weeks	16	0 ^[2]	0	0
Completed 24 weeks emicizumab treatment	1	35	34	58
Completed	1	1	0	0
Not completed	17	35	35	63
Withdrew from treatment due to AE	-	-	1	-
First emicizumab dose delayed	1	-	-	-
Ongoing treatment with emicizumab	16	35	34	63

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The milestone of "Switched to emicizumab 3 mg/kg/2 weeks" is only applicable to Arm C: No Prophylaxis.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The milestone of "Completed 24 weeks on No Prophylaxis" is only applicable to Arm C: No Prophylaxis.

Baseline characteristics

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Reporting group title

C: No Prophylaxis

Reporting group description

Reporting group title

A: Emicizumab 1.5 mg/kg/week

Reporting group description

Reporting group title

B: Emicizumab 3 mg/kg/2 weeks

Reporting group description

Reporting group title

D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)

Reporting group description

Reporting group values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Total
Number of subjects	18	36	35	63	152
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	1	0	0	7	8
Adults (18-64 years)	17	34	34	54	139
From 65-84 years	0	2	1	2	5
85 years and over	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	37.8 ± 12.9	39.8 ± 14.0	40.4 ± 11.4	36.4 ± 14.4	-
Sex: Female, Male
Units: Subjects
Female	0	0	0	0	0
Male	18	36	35	63	152
Number of Participants with <9 or ≥9 Bleeds in the Last 24 Weeks Prior to Study Entry
Units: Subjects
Less Than (<) 9 Bleeds\|	4	9	5	53	71
Greater Than or Equal To (≥) 9 Bleeds\|	14	27	30	10	81
Number of Target Joints in the Last 24 Weeks Prior to Study Entry
A target joint was defined as at least 3 bleeds into the same joint over the last 24 weeks prior to study entry.
Units: target joints
arithmetic mean (standard deviation)	2.2 ± 1.4	2.1 ± 1.4	2.2 ± 1.7	1.0 ± 1.6	-

End points

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Reporting group title

C: No Prophylaxis

Reporting group description

Reporting group title

A: Emicizumab 1.5 mg/kg/week

Reporting group description

Reporting group title

B: Emicizumab 3 mg/kg/2 weeks

Reporting group description

Reporting group title

D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)

Reporting group description

Subject analysis set title

Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This sub-group includes all participants from Arm C who switched to emicizumab prophylaxis after having completed at least 24 weeks on No Prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 3 mg/kg/2 weeks SC up to the end of study. The data reported was collected only during emicizumab prophylaxis treatment.

Subject analysis set title

Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768

Subject analysis set type

Sub-group analysis

Subject analysis set description

This sub-group includes historical data from participants in the non-interventional study (NIS) BH29768 who had received FVIII prophylaxis and were followed for a minimum of 24 weeks on the NIS prior to enrollment in Arm D of this study.

Subject analysis set title

Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This sub-group includes data from the same participants who had received FVIII prophylaxis in NIS BH29768 prior to study entry and then enrolled in Arm D of this study to receive emicizumab prophylaxis at a dose of 3 mg/kg/week subcutaneously (SC) for 4 weeks, followed by emicizumab 1.5 mg/kg/week SC until the end of study. The data reported was collected only during emicizumab prophylaxis treatment.

Subject analysis set title

A+Bnise: Pre-Study Episodic FVIII in NIS BH29768

Subject analysis set type

Sub-group analysis

Subject analysis set description

This sub-group includes historical data from participants in the non-interventional study (NIS) BH29768 who had received episodic FVIII treatment and were followed for a minimum of 24 weeks on the NIS prior to enrollment in Arms A or B of this study. A pooled analysis, as opposed to two separate analyses, was performed due to the small number of NIS episodic patients (NISE) randomized to either Arm A or B.

Subject analysis set title

A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This sub-group includes data from the same participants who had received episodic FVIII treatment in NIS BH29768 prior to study entry and then enrolled in Arms A or B of this study to receive emicizumab prophylaxis at a dose of 3 mg/kg/week subcutaneously (SC) for 4 weeks, followed by either emicizumab 1.5 mg/kg/week SC (Arm A) or emicizumab 3 mg/kg/2 weeks SC (Arm B) until the end of study. A pooled analysis, as opposed to two separate analyses, was performed due to the small number of NIS episodic patients (NISE) randomized to either Arm A or B. The data reported was collected only during emicizumab prophylaxis treatment.

Primary: Annualized Bleeding Rate (ABR) for Treated Bleeds

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End point title

Annualized Bleeding Rate (ABR) for Treated Bleeds

End point description

The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a negative binomial (NB) regression model, which accounts for different follow-up times, with the participant's number of bleeds as a function of randomization and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.

End point type

Primary

End point timeframe

From Baseline to at least 24 weeks

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: treated bleed rate per year
number (confidence interval 95%)	38.2 (22.86 to 63.76)	1.5 (0.89 to 2.47)	1.3 (0.75 to 2.25)	1.6 (1.07 to 2.44)

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

A: Emicizumab 1.5 mg/kg/week v C: No Prophylaxis

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.075

Notes
[1] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.017

upper limit

0.066

Notes
[2] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

Secondary: Annualized Bleeding Rate (ABR) for All Bleeds

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End point title

Annualized Bleeding Rate (ABR) for All Bleeds

End point description

The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. “All bleeds” comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: all bleed rate per year
number (confidence interval 95%)	47.6 (28.45 to 79.59)	2.5 (1.63 to 3.90)	2.6 (1.63 to 4.29)	3.3 (2.22 to 4.83)

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v A: Emicizumab 1.5 mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.028

upper limit

0.099

Notes
[3] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[4]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

0.103

Notes
[4] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value was obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

Secondary: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

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End point title

Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

End point description

The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study (length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A "joint bleed" is defined as a bleed reported as “joint” and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint; and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. It is considered a “treated joint bleed” if it is directly followed (no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: treated joint bleed rate per year
number (confidence interval 95%)	26.5 (14.67 to 47.79)	1.1 (0.59 to 1.89)	0.9 (0.44 to 1.67)	1.2 (0.70 to 2.01)

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v A: Emicizumab 1.5 mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.019

upper limit

0.085

Notes
[5] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.015

upper limit

0.07

Notes
[6] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

Secondary: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

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End point title

Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

End point description

The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A “treated spontaneous bleed” is a spontaneous bleed that is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: treated spontaneous bleed rate per year
number (confidence interval 95%)	15.6 (7.60 to 31.91)	1.0 (0.48 to 1.91)	0.3 (0.11 to 0.75)	0.5 (0.23 to 0.94)

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v A: Emicizumab 1.5 mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[7]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.025

upper limit

0.151

Notes
[7] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[8]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.056

Notes
[8] - Statistical significance is controlled at the 2-sided, 0.05 alpha level. The p-value is obtained via a global model with a 3-level categorical effect for treatment (emicizumab 1.5 mg/kg/week, emicizumab 3 mg/kg/2 weeks, or no prophylaxis).

Secondary: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

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End point title

Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

End point description

The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a NB regression model, which accounts for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A "target joint bleed" is defined as a bleed reported as a joint bleed into a target joint, defined as at least 3 bleeds into the same joint during the last 24 weeks prior to study entry. It is considered a “treated target joint bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)
Number of subjects analysed	18	36	35	63
Units: treated target joint bleed rate per year
number (confidence interval 95%)	13.0 (5.22 to 32.33)	0.6 (0.28 to 1.42)	0.7 (0.27 to 1.64)	0.6 (0.26 to 1.53)

ABR Ratio for Arm A versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm A versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm A versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v A: Emicizumab 1.5 mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[9]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.016

upper limit

0.143

Notes
[9] - Not controlled for type I error

ABR Ratio for Arm B versus Arm C

Statistical analysis description

H0 (null hypothesis): ABR Ratio for Arm B versus Arm C = 1. H1 (alternative hypothesis): ABR Ratio for Arm B versus Arm C ≠ 1.

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[10]

Method

Stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.018

upper limit

0.147

Notes
[10] - Not controlled for type I error

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with Factor VIII (FVIII) Prophylaxis (NISP)

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End point title

Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with Factor VIII (FVIII) Prophylaxis (NISP)

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds on study versus historical ABR in the NIS population previously treated with FVIII prophylaxis in NIS BH29768. The number of treated bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the participant's number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

End point values	Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768	Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)
Number of subjects analysed	48	48
Units: treated bleed rate per year
number (confidence interval 95%)	4.8 (3.22 to 7.09)	1.5 (0.98 to 2.33)

ABR Ratio - Dnisp: Emicizumab vs FVIII Prophylaxis

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1. H1 (alternative hypothesis): ABR Ratio ≠ 1. This is an intra-participant analysis of the ABR Ratio for a total of 48 participants (not 96) over two different periods: on study while receiving emicizumab prophylaxis (Dnisp: Emicizumab Prophylaxis) versus before study entry while receiving FVIII prophylaxis in NIS BH29768 (Dnisp: Pre-Study FVIII Prophylaxis).

Comparison groups

Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis) v Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[11]

Method

Non-stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.32

Confidence interval

level

95%

sides

2-sided

lower limit

0.195

upper limit

0.514

Notes
[11] - Statistical significance is controlled at the 2-sided, 0.05 alpha level.

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with FVIII Prophylaxis (NISP)

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End point title

Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with FVIII Prophylaxis (NISP)

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds on study versus historical ABR in the NIS population previously treated with FVIII prophylaxis in NIS BH29768. The number of all bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the participant’s number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. “All bleeds” comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

End point values	Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768	Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)
Number of subjects analysed	48	48
Units: all bleed rate per year
number (confidence interval 95%)	8.9 (5.72 to 13.87)	3.3 (2.17 to 5.06)

ABR Ratio - Dnisp: Emicizumab vs FVIII Prophylaxis

Statistical analysis description

Comparison groups

Dnisp: Pre-Study FVIII Prophylaxis in NIS BH29768 v Dnisp: Emicizumab Prophylaxis (Pre-Study FVIII Prophylaxis)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[12]

Method

Non-stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

0.626

Notes
[12] - Statistical significance is controlled at the 2-sided, 0.05 alpha level.

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

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End point title

Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds on study versus historical ABR in the NIS population previously treated with episodic FVIII in NIS BH29768. The number of treated bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the participant's number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

End point values	A+Bnise: Pre-Study Episodic FVIII in NIS BH29768	A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)
Number of subjects analysed	20	20
Units: treated bleed rate per year
number (confidence interval 95%)	34.4 (27.45 to 43.14)	1.0 (0.43 to 2.54)

ABR Ratio Emicizumab Prophylaxis vs Episodic FVIII

Statistical analysis description

H0 (null hypothesis): ABR Ratio = 1. H1 (alternative hypothesis): ABR Ratio ≠ 1. This is an intra-participant analysis of the ABR Ratio for a total of 20 participants (not 40) over two different periods: on study while receiving emicizumab prophylaxis (A+Bnise: Emicizumab Prophylaxis) versus before study entry while receiving episodic FVIII in NIS BH29768 (A+Bnise: Pre-Study Episodic FVIII).

Comparison groups

A+Bnise: Pre-Study Episodic FVIII in NIS BH29768 v A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[13]

Method

Non-stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.014

upper limit

0.067

Notes
[13] - Not controlled for type I error

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Top of page

End point title

Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

End point description

This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds on study versus historical ABR in the NIS population previously treated with episodic FVIII in NIS BH29768. The number of all bleeds over the efficacy period is presented as an ABR that was assessed using a NB regression model, which accounts for different follow-up times, with the participant’s number of bleeds as a function of treatment and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes a repeated statement to account for intra-participant comparison. “All bleeds” comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded.

End point type

Secondary

End point timeframe

From Baseline to at least 24 weeks

End point values	A+Bnise: Pre-Study Episodic FVIII in NIS BH29768	A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)
Number of subjects analysed	20	20
Units: all bleed rate per year
number (confidence interval 95%)	39.6 (31.94 to 49.04)	1.6 (0.85 to 2.92)

ABR Ratio Emicizumab Prophylaxis vs Episodic FVIII

Statistical analysis description

Comparison groups

A+Bnise: Pre-Study Episodic FVIII in NIS BH29768 v A+Bnise: Emicizumab Prophylaxis (Pre-study Episodic FVIII)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[14]

Method

Non-stratified Wald test

Parameter type

ABR Ratio

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.023

upper limit

0.068

Notes
[14] - Not controlled for type I error

Secondary: Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

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End point title

Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25 ^[15]

End point description

The Haem-A-QoL questionnaire is rated by participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The score for each domain ranges from 0 to 100; lower scores reflective of better quality of life. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health). The means were derived via an ANCOVA model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term. Analysis includes all adult participants who provided responses at Baseline and Week 25.

End point type

Secondary

End point timeframe

Baseline, Week 25

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants in Arms A, B, and C were randomized in this study.

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks
Number of subjects analysed	13	34	29
Units: units on a scale
arithmetic mean (standard deviation)	44.32 ± 17.15	31.81 ± 27.86	28.35 ± 25.57

Difference in Adjusted Means (Arm C vs. Arm A)

Comparison groups

C: No Prophylaxis v A: Emicizumab 1.5 mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0891 ^[16]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

12.51

Confidence interval

level

95%

sides

2-sided

lower limit

-1.96

upper limit

26.98

Notes
[16] - Statistical significance is controlled at the 2-sided, 0.05 alpha level.

Difference in Adjusted Means (Arm C vs. Arm B)

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0349 ^[17]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

15.97

Confidence interval

level

95%

sides

2-sided

lower limit

1.16

upper limit

30.78

Notes
[17] - Not controlled for type I error

Secondary: Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

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End point title

Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25 ^[18]

End point description

The Haem-A-QoL questionnaire is rated by participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The score for each domain ranges from 0 to 100; lower scores reflective of better quality of life. Haem-A-QoL Total Score is the average of all domain scores (range 0 to 100, lower scores reflective of better quality of life). The means were derived via an ANCOVA model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term. Analysis includes all adult participants who provided responses at Baseline and Week 25.

End point type

Secondary

End point timeframe

Baseline, Week 25

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants in Arms A, B, and C were randomized in this study.

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks
Number of subjects analysed	13	34	29
Units: units on a scale
arithmetic mean (standard deviation)	29.95 ± 13.56	24.04 ± 15.26	21.39 ± 12.64

Difference in Adjusted Means (Arm C vs. Arm A)

Comparison groups

C: No Prophylaxis v A: Emicizumab 1.5 mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1269 ^[19]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

5.91

Confidence interval

level

95%

sides

2-sided

lower limit

-1.72

upper limit

13.55

Notes
[19] - Not controlled for type I error

Difference in Adjusted Means (Arm C vs. Arm B)

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0317 ^[20]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

8.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

16.35

Notes
[20] - Not controlled for type I error

Secondary: European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25

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End point title

European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25 ^[21]

End point description

EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L VAS. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. The means were derived via an ANCOVA model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term. Analysis includes all participants who provided responses at Baseline and Week 25.

End point type

Secondary

End point timeframe

Baseline, Week 25

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants in Arms A, B, and C were randomized in this study.

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks
Number of subjects analysed	14	34	29
Units: units on a scale
arithmetic mean (standard deviation)	72.57 ± 8.20	76.61 ± 20.99	81.72 ± 15.55

Difference in Adjusted Means (Arm C vs. Arm A)

Comparison groups

C: No Prophylaxis v A: Emicizumab 1.5 mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3402 ^[22]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-4.04

Confidence interval

level

95%

sides

2-sided

lower limit

-12.43

upper limit

4.35

Notes
[22] - Not controlled for type I error

Difference in Adjusted Means (Arm C vs. Arm B)

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0373 ^[23]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-9.15

Confidence interval

level

95%

sides

2-sided

lower limit

-17.74

upper limit

-0.55

Notes
[23] - Not controlled for type I error

Secondary: EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25

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End point title

EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25 ^[24]

End point description

EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: EQ-5D-5L health state profile (descriptive system) and EQ-5D-5L VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term. This analysis includes all participants who provided responses at Baseline and Week 25.

End point type

Secondary

End point timeframe

Baseline, Week 25

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants in Arms A, B, and C were randomized in this study.

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks
Number of subjects analysed	14	34	29
Units: units on a scale
arithmetic mean (standard deviation)	0.63 ± 0.20	0.76 ± 0.24	0.76 ± 0.18

Difference in Adjusted Means (Arm C vs. Arm A)

Comparison groups

C: No Prophylaxis v A: Emicizumab 1.5 mg/kg/week

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006 ^[25]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

-0.04

Notes
[25] - Not controlled for type I error

Difference in Adjusted Means (Arm C vs. Arm B)

Comparison groups

C: No Prophylaxis v B: Emicizumab 3 mg/kg/2 weeks

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0059 ^[26]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.23

upper limit

-0.04

Notes
[26] - Not controlled for type I error

Secondary: Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) at Week 25

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End point title

Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) at Week 25

End point description

The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children’s health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. The analysis was not performed due to the small number of adolescents randomized or enrolled in this study.

End point type

Secondary

End point timeframe

Week 25

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	0 ^[27]	0 ^[28]	0 ^[29]	0 ^[30]	0 ^[31]
Units: units on a scale
arithmetic mean (standard deviation)	±	±	±	±	±

Notes
[27] - Analysis was not performed due to small number of adolescents randomized to this study.
[28] - Analysis was not performed due to small number of adolescents randomized to this study.
[29] - Analysis was not performed due to small number of adolescents randomized to this study.
[30] - Analysis was not performed due to small number of adolescents enrolled in this study.
[31] - Analysis was not performed due to small number of adolescents randomized to this study.

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least One Adverse Event

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End point title

Percentage of Participants With at Least One Adverse Event

End point description

The percentage of participants experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	33.3	94.4	85.7	87.3	50.0

No statistical analyses for this end point

Secondary: Percentage of Participants With Grade ≥3 Adverse Events

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End point title

Percentage of Participants With Grade ≥3 Adverse Events

End point description

The World Health Organization (WHO) toxicity grading scale will be used for assessing adverse event severity. For adverse events that are not specifically listed in the WHO toxicity grading scale, a grade 3 adverse event is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a grade 4 adverse event is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	5.6	8.3	11.4	9.3	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events Leading to Withdrawal From Treatment

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End point title

Percentage of Participants With Adverse Events Leading to Withdrawal From Treatment

End point description

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	2.9	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events of Changes from Baseline in Vital Signs

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End point title

Percentage of Participants With Adverse Events of Changes from Baseline in Vital Signs

End point description

The percentage of participants with adverse events of changes from baseline in vital signs is reported here. Vital signs measurements consisted of heart and respiratory rate, temperature, and systolic and diastolic blood pressures, with an abnormal vital sign value being outside of the normal range. An abnormal vital sign result is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events of Changes from Baseline in Physical Examination Findings

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End point title

Percentage of Participants With Adverse Events of Changes from Baseline in Physical Examination Findings

End point description

Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events of Abnormal Laboratory Values

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End point title

Percentage of Participants With Adverse Events of Abnormal Laboratory Values

End point description

The percentage of participants with adverse events of abnormal laboratory values is reported here. An abnormal laboratory value is defined as a laboratory test result outside of the normal range for hematology or serum chemistries. It is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Local Injection-Site Reactions

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End point title

Percentage of Participants With Local Injection-Site Reactions

End point description

Local adverse events that occurred within 24 hours after study drug administration and, in the investigator’s opinion, were judged to be related to study drug injection, were captured as an “injection-site reaction” on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a “local injection-site reaction.” At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	25.0	20.0	33.3	12.5

No statistical analyses for this end point

Secondary: Percentage of Participants With Thromboembolic Events

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End point title

Percentage of Participants With Thromboembolic Events

End point description

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Thrombotic Microangiopathy

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End point title

Percentage of Participants With Thrombotic Microangiopathy

End point description

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions

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End point title

Percentage of Participants With Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions

End point description

At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

End point values	C: No Prophylaxis	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	18	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-Emicizumab Antibodies

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End point title

Percentage of Participants With Anti-Emicizumab Antibodies ^[32]

End point description

A validated ELISA method was used to analyze the levels of anti-emicizumab antibodies in plasma. A sample was considered positive for anti-emicizumab antibodies if the test result reached or exceeded a pre-determined threshold. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Samples were collected at baseline and only during treatment with emicizumab. Participants in Arm C: No Prophylaxis did not receive emicizumab for the first 24 weeks they were on the study; after completing 24 weeks, they were given the opportunity to cross over to Arm Cemi: Emicizumab 3 mg/kg/2 weeks (Switch from No Prophylaxis).

End point values	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	35	32	60	6
Units: percentage of participants
number (not applicable)	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With De Novo Development of Factor VIII (FVIII) Inhibitors

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End point title

Percentage of Participants With De Novo Development of Factor VIII (FVIII) Inhibitors ^[33]

End point description

Levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A participant was considered to have developed de novo FVIII inhibitors if the inhibitor levels detected in a post-baseline sample reached or exceeded a pre-determined threshold. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

From Baseline up to 24 weeks after last dose of study drug (up to 2.5 years)

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Samples were collected at baseline and only during treatment with emicizumab. Participants in Arm C: No Prophylaxis did not receive emicizumab for the first 24 weeks they were on the study; after completing 24 weeks, they were given the opportunity to cross over to Arm Cemi: Emicizumab 3 mg/kg/2 weeks (Switch from No Prophylaxis).

End point values	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	36	35	63	16
Units: percentage of participants
number (not applicable)	0	0	0	0

No statistical analyses for this end point

Secondary: Trough Plasma Concentration (Ctrough) of Emicizumab

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End point title

Trough Plasma Concentration (Ctrough) of Emicizumab ^[34]

End point description

Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantitation (LLOQ) was 0.1 micrograms per milliliter (μg/mL). The pharmacokinetic (PK) evaluable population included all participants who received at least one dose of emicizumab and had at least one post-dose emicizumab concentration result. Here, n=participants with available data for this endpoint at specified timepoints in each arm (A, B, D, Cemi), respectively. Here, '99999' represents data not calculable due to single participant; '9999' represents data collection not planned for this arm at this timepoint; and '999' represents no data available because either the measurements were below LLOQ or no patient samples were available at that timepoint. At the clinical cut-off date for primary analysis (15 Sep 2017), data was collected over a period of approximately 1 year.

End point type

Secondary

End point timeframe

Predose (Hour 0) on every week during Weeks 1-4, every 2 weeks during Weeks 5-8, every 4 weeks during Weeks 9-24, every 8 weeks during Weeks 25-48, every 12 weeks thereafter up to the end of the study (up to 2 years)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Samples were collected at baseline and only during treatment with emicizumab. Participants in Arm C: No Prophylaxis did not receive emicizumab for the first 24 weeks they were on the study; after completing 24 weeks, they were given the opportunity to cross over to Arm Cemi: Emicizumab 3 mg/kg/2 weeks (Switch from No Prophylaxis).

End point values	A: Emicizumab 1.5 mg/kg/week	B: Emicizumab 3 mg/kg/2 weeks	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	Cemi: Emicizumab 3 mg/kg/2 weeks (Switch From No Prophylaxis)
Number of subjects analysed	36	35	63	16
Units: micrograms per milliliter (μg/mL)
arithmetic mean (standard deviation)
Week 1 (n=35, 33, 61, 0)	999 ± 999	999 ± 999	999 ± 999	9999 ± 9999
Week 2 (n=36, 35, 61, 0)	16.3 ± 6.1	16.8 ± 5.9	17.4 ± 5.4	9999 ± 9999
Week 3 (n=36, 35, 62, 0)	29.1 ± 9.3	29.2 ± 6.5	30.5 ± 8.7	9999 ± 9999
Week 4 (n=35, 34, 60, 0)	41.6 ± 11.9	41.8 ± 9.5	42.2 ± 9.4	9999 ± 9999
Week 5 (n=34, 35, 62, 0)	48.0 ± 13.7	48.8 ± 12.3	54.5 ± 12.5	9999 ± 9999
Week 7 (n=32, 33, 60, 0)	47.9 ± 16.1	48.4 ± 11.4	52.4 ± 13.4	9999 ± 9999
Week 9 (n=33, 33, 63, 0)	49.0 ± 16.4	47.1 ± 13.7	55.1 ± 16.1	9999 ± 9999
Week 13 (n=33, 31, 59, 0)	48.7 ± 18.3	48.7 ± 15.6	56.0 ± 15.7	9999 ± 9999
Week 17 (n=31, 32, 56, 0)	51.7 ± 18.8	49.6 ± 17.2	55.4 ± 16.8	9999 ± 9999
Week 21 (n=29, 33, 58, 0)	48.0 ± 17.7	46.7 ± 15.3	55.8 ± 16.3	9999 ± 9999
Week 25 (n=28, 26, 47, 13)	51.0 ± 22.2	46.3 ± 18.0	55.0 ± 17.5	999 ± 999
Week 26 (n=0, 0, 0, 13)	9999 ± 9999	9999 ± 9999	9999 ± 9999	19.4 ± 9.2
Week 27 (n=0, 0, 0, 12)	9999 ± 9999	9999 ± 9999	9999 ± 9999	32.9 ± 14.5
Week 28 (n=0, 0, 0, 9)	9999 ± 9999	9999 ± 9999	9999 ± 9999	46.7 ± 17.4
Week 29 (n=0, 0, 0, 9)	9999 ± 9999	9999 ± 9999	9999 ± 9999	59.2 ± 25.3
Week 31 (n=0, 0, 0, 9)	9999 ± 9999	9999 ± 9999	9999 ± 9999	52.9 ± 17.3
Week 33 (n=12, 15, 29, 7)	61.8 ± 30.4	47.6 ± 19.5	59.9 ± 19.3	47.0 ± 17.9
Week 37 (n=0, 0, 0, 7)	9999 ± 9999	9999 ± 9999	9999 ± 9999	39.2 ± 17.6
Week 41 (n=6, 10, 10, 4)	45.2 ± 17.9	47.1 ± 19.7	54.9 ± 13.4	40.3 ± 6.4
Week 45 (n=0, 0, 0, 4)	9999 ± 9999	9999 ± 9999	9999 ± 9999	43.8 ± 9.4
Week 49 (n=2, 2, 1, 0)	62.3 ± 30.8	43.6 ± 13.2	54.1 ± 99999	999 ± 999

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline up to the clinical cut-off date (15 Sep 2017) for primary analysis (approximately 1 year)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

A: Emicizumab 1.5 mg/kg/week

Reporting group description

Participants who received episodic treatment with FVIII prior to study entry will receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for 4 weeks, followed by 1.5 mg/kg/week emicizumab SC until the end of study (maximum up to 2 years).

Reporting group title

C: No Prophylaxis

Reporting group description

Participants who received episodic treatment with FVIII prior to study entry will be randomized to continue episodic FVIII treatment when they start the trial; they will have the opportunity to switch to emicizumab prophylaxis after 24 weeks on-study.

Reporting group title

Cemi: Emicizumab 3 mg/kg/2 weeks (From No Prophylaxis)

Reporting group description

This arm includes Arm C participants who switched to emicizumab prophylaxis after completing at least 24 weeks on No Prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 3 mg/kg/2 weeks SC up to the end of study. Data reported represents data collected during emicizumab treatment only.

Reporting group title

D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)

Reporting group description

Participants who received FVIII prophylaxis prior to study entry will receive emicizumab prophylaxis at a dose of 3 mg/kg/week SC for 4 weeks, followed by 1.5 mg/kg/week emicizumab SC until the end of study (maximum up to 2 years).

Reporting group title

B: Emicizumab 3 mg/kg/2 weeks

Reporting group description

Participants who received episodic treatment with FVIII prior to study entry will receive emicizumab prophylaxis at a dose of 3 mg/kg/week SC for 4 weeks, followed by 3 mg/kg/2 weeks emicizumab SC until the end of study (maximum up to 2 years).

Serious adverse events	A: Emicizumab 1.5 mg/kg/week	C: No Prophylaxis	Cemi: Emicizumab 3 mg/kg/2 weeks (From No Prophylaxis)	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	B: Emicizumab 3 mg/kg/2 weeks
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 36 (2.78%)	1 / 18 (5.56%)	0 / 16 (0.00%)	8 / 63 (12.70%)	3 / 35 (8.57%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 63 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 36 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 63 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Putamen haemorrhage
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 63 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Mallory-Weiss syndrome
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Groin pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device loosening
subjects affected / exposed	1 / 36 (2.78%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 63 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subperiosteal abscess
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	A: Emicizumab 1.5 mg/kg/week	C: No Prophylaxis	Cemi: Emicizumab 3 mg/kg/2 weeks (From No Prophylaxis)	D: Emicizumab 1.5 mg/kg/week (Pre-study FVIII Prophylaxis)	B: Emicizumab 3 mg/kg/2 weeks
Total subjects affected by non serious adverse events
subjects affected / exposed	26 / 36 (72.22%)	5 / 18 (27.78%)	8 / 16 (50.00%)	43 / 63 (68.25%)	23 / 35 (65.71%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 63 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	2
Aspartate aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 63 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	2
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	3 / 63 (4.76%)	2 / 35 (5.71%)
occurrences all number	0	0	1	3	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papilloma
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 63 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	0
Injury, poisoning and procedural complications
Bite
subjects affected / exposed	0 / 36 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 63 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0
Contusion
subjects affected / exposed	2 / 36 (5.56%)	0 / 18 (0.00%)	0 / 16 (0.00%)	4 / 63 (6.35%)	1 / 35 (2.86%)
occurrences all number	14	0	0	5	2
Excoriation
subjects affected / exposed	0 / 36 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 63 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0
Muscle strain
subjects affected / exposed	2 / 36 (5.56%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences all number	2	0	0	1	0
Laceration
subjects affected / exposed	1 / 36 (2.78%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences all number	1	0	1	1	0
Ligament sprain
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	4 / 63 (6.35%)	0 / 35 (0.00%)
occurrences all number	0	0	1	5	0
Tooth fracture
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences all number	0	0	1	1	0
Nervous system disorders
Headache
subjects affected / exposed	3 / 36 (8.33%)	1 / 18 (5.56%)	1 / 16 (6.25%)	8 / 63 (12.70%)	4 / 35 (11.43%)
occurrences all number	6	1	1	17	19
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	9 / 36 (25.00%)	0 / 18 (0.00%)	2 / 16 (12.50%)	20 / 63 (31.75%)	7 / 35 (20.00%)
occurrences all number	35	0	2	29	17
Pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 63 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	1	0	1
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 63 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	0	0	0	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 36 (5.56%)	0 / 18 (0.00%)	2 / 16 (12.50%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences all number	2	0	3	1	0
Diarrhoea
subjects affected / exposed	1 / 36 (2.78%)	1 / 18 (5.56%)	1 / 16 (6.25%)	1 / 63 (1.59%)	2 / 35 (5.71%)
occurrences all number	1	2	1	1	3
Nausea
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	3 / 63 (4.76%)	2 / 35 (5.71%)
occurrences all number	0	0	0	3	2
Vomiting
subjects affected / exposed	0 / 36 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 63 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	1 / 36 (2.78%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 63 (1.59%)	1 / 35 (2.86%)
occurrences all number	1	0	1	1	1
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 36 (2.78%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 63 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	0	0	0	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 36 (19.44%)	1 / 18 (5.56%)	1 / 16 (6.25%)	14 / 63 (22.22%)	6 / 35 (17.14%)
occurrences all number	19	1	3	35	13
Back pain
subjects affected / exposed	1 / 36 (2.78%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 63 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	1	0	0	1
Musculoskeletal stiffness
subjects affected / exposed	0 / 36 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 63 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	0	0
Pain in extremity
subjects affected / exposed	1 / 36 (2.78%)	1 / 18 (5.56%)	0 / 16 (0.00%)	3 / 63 (4.76%)	3 / 35 (8.57%)
occurrences all number	1	2	0	3	3
Infections and infestations
Conjunctivitis
subjects affected / exposed	1 / 36 (2.78%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 63 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	1	0	0	1
Influenza
subjects affected / exposed	1 / 36 (2.78%)	0 / 18 (0.00%)	0 / 16 (0.00%)	5 / 63 (7.94%)	3 / 35 (8.57%)
occurrences all number	1	0	0	5	3
Gastric infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences all number	0	0	1	1	0
Localised infection
subjects affected / exposed	0 / 36 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 63 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	0	0	1
Nasopharyngitis
subjects affected / exposed	2 / 36 (5.56%)	1 / 18 (5.56%)	0 / 16 (0.00%)	10 / 63 (15.87%)	6 / 35 (17.14%)
occurrences all number	3	1	0	13	8
Pharyngitis
subjects affected / exposed	3 / 36 (8.33%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 63 (3.17%)	1 / 35 (2.86%)
occurrences all number	3	0	0	4	1
Sinusitis
subjects affected / exposed	0 / 36 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	1 / 63 (1.59%)	0 / 35 (0.00%)
occurrences all number	0	3	1	1	0
Upper respiratory tract infection
subjects affected / exposed	4 / 36 (11.11%)	1 / 18 (5.56%)	0 / 16 (0.00%)	8 / 63 (12.70%)	4 / 35 (11.43%)
occurrences all number	4	2	0	8	4

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Were there any global substantial amendments to the protocol? Yes

12 Sep 2016

The main changes to the protocol are as follows: - The specific factor VIII (FVIII) prophylactic dose and frequency was removed from the definition for FVIII prophylaxis regimen for the inclusion criterion for patients previously treated with FVIII prophylaxis to be enrolled in Arm D.; - Modified dose escalation criteria to more precisely define the subpopulation who may benefit from an increased dose of emicizumab; - Added clarification regarding the efficacy analyses that will be performed for treated bleeds (i.e., treated with coagulation factors) and all bleeds (i.e., both treated and not treated with coagulation factors) given that some patients may report bleeds that they did not treat. In addition, rate of spontaneous bleeds was added as a secondary endpoint.; - Added safety updates regarding a case of atypical hemolytic uremic syndrome (aHUS) and a patient who developed cavernous sinus thrombosis. Both occurred in patients with hemophilia A with FVIII inhibitors receiving bypassing agents.; - The optional interim analysis section was removed based on the anticipated study timelines, as no interim analyses are expected for this study.; - Provided the option for patients to potentially combine emicizumab volumes (if necessary) from up to two vials into 1 syringe to reduce the number of subcutaneous injections they may require.

30 Nov 2016

The main changes to the protocol are as follows: - The safety sections were updated with the most recent safety information regarding 2 cases of thrombotic microangiopathy (TMA) and 2 patients who developed thromboembolic events in Study BH29884. Both occurred in patients with hemophilia A with FVIII inhibitors receiving bypassing agents. The section for risks associated with emicizumab was updated accordingly, and microangiopathic hemolytic anemia/TMA is newly classified as an adverse event of special interest.; - Although factor VIII (FVIII) and activated prothrombin complex concentrate (aPCC) are fundamentally different in their potential interaction with emicizumab, the amended protocol points investigators to the fact that circulating emicizumab increases patients’ coagulation potential and provides suggestions about the use of FVIII in conjunction with emicizumab.; - The van Elteren test will be used as back-up statistical method for the primary analysis instead of the Wilcoxon rank sum test to allow a stratified analysis to be performed.; - Although the use of bypassing agents is unlikely in patients without inhibitors, for completeness and clarity, the amended protocol includes guidelines for their use in patients receiving emicizumab, including dosage and requirements for laboratory monitoring.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Patients Without Inhibitors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Annualized Bleeding Rate (ABR) for Treated Bleeds

Primary: Annualized Bleeding Rate (ABR) for Treated Bleeds

Secondary: Annualized Bleeding Rate (ABR) for All Bleeds

Secondary: Annualized Bleeding Rate (ABR) for All Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

Secondary: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with Factor VIII (FVIII) Prophylaxis (NISP)

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with Factor VIII (FVIII) Prophylaxis (NISP)

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with FVIII Prophylaxis (NISP)

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the Non-Interventional Study Population Previously Treated with FVIII Prophylaxis (NISP)

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Secondary: Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Secondary: Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants from the NIS Population Previously Treated with Episodic FVIII (NISE)

Secondary: Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

Secondary: Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

Secondary: Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

Secondary: Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25

Secondary: European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25

Secondary: European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25

Secondary: EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25

Secondary: EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25

Secondary: Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) at Week 25

Secondary: Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) at Week 25

Secondary: Percentage of Participants With at Least One Adverse Event

Secondary: Percentage of Participants With at Least One Adverse Event

Secondary: Percentage of Participants With Grade ≥3 Adverse Events

Secondary: Percentage of Participants With Grade ≥3 Adverse Events

Secondary: Percentage of Participants With Adverse Events Leading to Withdrawal From Treatment

Secondary: Percentage of Participants With Adverse Events Leading to Withdrawal From Treatment

Secondary: Percentage of Participants With Adverse Events of Changes from Baseline in Vital Signs

Secondary: Percentage of Participants With Adverse Events of Changes from Baseline in Vital Signs

Secondary: Percentage of Participants With Adverse Events of Changes from Baseline in Physical Examination Findings

Secondary: Percentage of Participants With Adverse Events of Changes from Baseline in Physical Examination Findings

Secondary: Percentage of Participants With Adverse Events of Abnormal Laboratory Values

Secondary: Percentage of Participants With Adverse Events of Abnormal Laboratory Values

Secondary: Percentage of Participants With Local Injection-Site Reactions

Secondary: Percentage of Participants With Local Injection-Site Reactions

Secondary: Percentage of Participants With Thromboembolic Events

Secondary: Percentage of Participants With Thromboembolic Events

Secondary: Percentage of Participants With Thrombotic Microangiopathy

Secondary: Percentage of Participants With Thrombotic Microangiopathy

Secondary: Percentage of Participants With Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions

Secondary: Percentage of Participants With Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions

Secondary: Percentage of Participants With Anti-Emicizumab Antibodies

Secondary: Percentage of Participants With Anti-Emicizumab Antibodies

Secondary: Percentage of Participants With De Novo Development of Factor VIII (FVIII) Inhibitors

Secondary: Percentage of Participants With De Novo Development of Factor VIII (FVIII) Inhibitors

Secondary: Trough Plasma Concentration (Ctrough) of Emicizumab

Secondary: Trough Plasma Concentration (Ctrough) of Emicizumab

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Patients Without Inhibitors